Methods and apparatus for controlling neurostimulation using evoked physiologic events

ABSTRACT

A neurostimulation system provides for capture verification and stimulation intensity adjustment to ensure effectiveness of vagus nerve stimulation in modulating one or more target functions in a patient. In various embodiments, stimulation is applied to the vagus nerve, and evoked responses are detected to verify that the stimulation captures the vagus nerve and to adjust one or more stimulation parameters that control the stimulation intensity.

CLAIM OF PRIORITY

This application claims the benefit of priority under 35 U.S.C. §119(e)of U.S. Provisional Patent Application Ser. No. 61/356,251, filed onJun. 18, 2010, which is herein incorporated by reference in itsentirety.

CROSS REFERENCE TO RELATED APPLICATIONS

The following commonly assigned U.S. patent applications are related,and are herein incorporated by reference in their entirety: “METHODS ANDAPPARATUS FOR CONTROLLING NEUROSTIMULATION USING EVOKED NEURALRESPONSES,” Ser. No. ______, filed on Jun. __, 2011 and “METHODS ANDAPPARATUS FOR ADJUSTING NEUROSTIMULATION INTENSITY USING EVOKEDRESPONSES,” Ser. No. ______, filed on Jun. __, 2011.

TECHNICAL FIELD

This document relates generally to neurostimulation and moreparticularly to a neurostimulation system that detects evoked responsesand uses the detected evoked responses for capture verification andparameter adjustment.

BACKGROUND

Vagus nerve stimulation has been applied to modulate various physiologicfunctions and treat various diseases. One example is the modulation ofcardiac functions in a patient suffering heart failure or myocardialinfarction. The myocardium is innervated with sympathetic andparasympathetic nerves including the cardiac branches of the vagusnerve. Activities in the vagus nerve, including artificially appliedelectrical stimuli, modulate the heart rate and contractility (strengthof the myocardial contractions). Electrical stimulation applied to thevagus nerve is known to decrease the heart rate and the contractility,lengthening the systolic phase of a cardiac cycle, and shortening thediastolic phase of the cardiac cycle. This ability of vagus nervestimulation is utilized, for example, to control myocardial remodeling.

In addition to treating cardiac disorders such as myocardial remodeling,vagus nerve stimulation is also known to be effective in treatingdisorders including, but not limited to, depression, anorexianervosa/eating disorders, pancreatic function, epilepsy, hypertension,inflammatory disease, and diabetes. To ensure efficacy of a vagus nervestimulation therapy, there is a need to verify that the stimulationactivates the target branches of the vagus nerve and control thestimulation parameters to result in effective modulation of targetfunctions.

SUMMARY

A neurostimulation system provides for capture verification andstimulation intensity adjustment to ensure effectiveness of vagus nervestimulation in modulating one or more target functions in a patient. Invarious embodiments, stimulation is applied to the vagus nerve, andevoked responses are detected to verify that the stimulation capturesthe vagus nerve and to adjust one or more stimulation parameters thatcontrol the stimulation intensity.

In one embodiment, a system for delivering neurostimulation includes astimulation output circuit, an evoked response detection circuit, and acontrol circuit. The stimulation output circuit deliversneurostimulation pulses to a vagus nerve. The evoked response detectioncircuit receives a physiological signal indicative of evoked responsesbeing physiologic events evoked by the neurostimulation pulses anddetects the evoked responses using the physiological signal and one ormore detection thresholds. The control circuit includes a sensingparameter adjustor that adjusts the one or more detection thresholdsusing the detected evoked responses and a stored baseline response.

In one embodiment, a method for delivering neurostimulation is provided.Neurostimulation pulses are delivered to a vagus nerve. A physiologicalsignal indicative of evoked responses is sensed. The evoked responsesare each a physiologic event evoked by one of the neurostimulationpulses. The evoked responses are detected by comparing the physiologicalsignal to one or more detection thresholds. The one or more detectionthresholds are detected using the detected evoked neural responses.

This Summary is an overview of some of the teachings of the presentapplication and not intended to be an exclusive or exhaustive treatmentof the present subject matter. Further details about the present subjectmatter are found in the detailed description and appended claims. Otheraspects of the invention will be apparent to persons skilled in the artupon reading and understanding the following detailed description andviewing the drawings that form a part thereof. The scope of the presentinvention is defined by the appended claims and their legal equivalents.

BRIEF DESCRIPTION OF THE DRAWINGS

The drawings illustrate generally, by way of example, variousembodiments discussed in the present document. The drawings are forillustrative purposes only and may not be to scale.

FIG. 1 is an illustration of an embodiment of a vagus nerve stimulationsystem and portions of an environment in which the system is used.

FIG. 2 is a block diagram illustrating an embodiment of a vagus nervestimulation system providing for detection of evoked responses.

FIG. 3 is a block diagram illustrating another embodiment of the vagusnerve stimulation system of FIG. 2.

FIG. 4 is an illustration of an embodiment of an implantable systemincluding the vagus nerve stimulation system and portions of anenvironment in which the implantable system is used.

FIG. 5 is a block diagram illustrating an embodiment of the implantablesystem of FIG. 4

FIG. 6 is an illustration of evoked responses to a neurostimlationpulse.

FIG. 7 is an illustration of evoked responses to neurostimlation pulsesof various amplitudes.

FIG. 8 is an illustration showing various stimulation thresholds.

FIG. 9 is a block diagram illustrating an embodiment of a circuit fordetecting evoked neural responses.

FIG. 10 is an illustration of au evoked neural response and detectionwindows.

FIG. 11 is a block diagram illustrating an embodiment of a system fordetecting evoked neural responses.

FIG. 12 is a block diagram illustrating an embodiment of a circuit fordetecting evoked muscular responses.

FIG. 13 is a block diagram illustrating another embodiment of a systemfor detecting evoked muscular responses.

FIG. 14 is a block diagram illustrating an embodiment of a circuit forsensing various laryngeal signals.

FIG. 15 is a flow chart illustrating an embodiment of a method forautomatic threshold adjustment for evoked response detection duringvagus nerve stimulation,

FIG. 16 is a flow chart illustrating an embodiment of a method foradjusting stimulation intensity for vagus nerve stimulation.

FIG. 17 is an illustration showing an example of a relationship betweenstimulation thresholds for two types of fibers of the vagus nerve.

FIG. 18 is a flow chart illustrating an embodiment of a method foradjusting stimulation intensity for vagus nerve stimulation duringimplantation of an implantable medical device into a patient.

FIG. 19 is a flow chart illustrating an embodiment of a method foradjusting stimulation intensity for vagus nerve stimulation duringfollow-up visits by the patient using the implantable medical device.

FIG. 20 is a flow chart illustrating an embodiment of a method forautomatic capture verification for vagus nerve stimulation.

DETAILED DESCRIPTION

In the following detailed description, reference is made to theaccompanying drawings which form a part hereof, and in which is shown byway of illustration specific embodiments in which the invention may bepracticed. These embodiments are described in sufficient detail toenable those skilled in the art to practice the invention, and it is tobe understood that the embodiments may be combined, or that otherembodiments may be utilized and that structural, logical and electricalchanges may be made without departing from the spirit and scope of thepresent invention. The following detailed description provides examples,and the scope of the present invention is defined by the appended claimsand their legal equivalents.

It should be noted that references to “an”, “one”, or “various”embodiments in this disclosure are not necessarily to the sameembodiment, and such references contemplate more than one embodiment.

This document discusses a method and system for deliveringneurostimulation to modulate one or more target functions and detectingone or more physiological responses evoked by the neurostimulation. Thedetection of an evoked physiological response indicates that the nerveis captured by the stimulation. In various embodiments, each evokedphysiological response is detected from a neural signal sensed from thenerve and/or from another physiological signal capable of being asurrogate of the neural signal. While a vagus nerve stimulation isspecifically discussed in this document as an example, the presentmethod and system generally applies to stimulation of various targetnerves.

The vagus nerve originates in the medulla and targets multiple organs ina person's body through a complex functional innervation pattern. Thereare both efferent and afferent nerve fibers within the vagus nerve trunkthat convey neural activities to and from visceral organs such as theesophagus, gastrointestinal tract, kidney and pancreas (abdominal branchof vagus), thoracic organs such as the heart and lungs (thoracic branchof vagus), and voluntary muscles of the neck and multiple segments ofthe upper airway (recurrent laryngeal nerve, RLN). In one embodiment inwhich vagus nerve stimulation is delivered to modulate one or morecardiovascular functions, examples of evoked responses indicating thatthe vagus nerve is captured include neural signals sensed from the vagusnerve and signals indicative of laryngeal activities.

Fibers of the vagus nerve include A-fibers (myelinated fibers, alsoreferred to as A-type fibers), B-fibers (myelinated parasympatheticfibers, also referred to as B-type fibers), and C-fibers (unmyelinatedfibers, also referred to as C-type fibers), as summarized in Table 1. Itis believed that functions of most of the visceral and thoracic organsare modulated by vagus nerve stimulation through activation of theB-fibers, while activation of the A-fibers results in evoked laryngealactivities. As verified by experimental data, the stimulation intensityrequired for activating the B-fibers (stimulation threshold forB-fibers) is higher than the stimulation intensity required foractivating the A-fibers (stimulation threshold for A-fibers) because thediameters of the B-fibers arc smaller than the diameters of theA-fibers. The stimulation intensity required for activating the C-fibers(stimulation threshold for C-fibers) is highest because the C-fibershave the smallest diameter among those three types of fibers.

TABLE 1 Summary of Vagus Nerve Fiber Type Properties. A-Fibers B-FibersC-Fibers Diameter (μm) 5-20 1-3 0.2-2 Myelinated Yes Yes No ConductionVelocity (m/s) 30-120  3-20 0.3-2 Per-Unit Latencies (ms/cm) 0.08-0.3 0.5-3.3   5-33.3

The present method and system senses various signals indicative of theevoked neural and/or muscular responses to vagus nerve stimulation toensure activation of the B-fibers. In various embodiments, vagus nervestimulation is applied to modulate one or more cardiovascular functions,and one or more signals indicative of evoked neural responses of thevagus nerve and/or evoked muscular responses of the laryngeal musclesare sensed. Capture of the vagus nerve is verified by detected evokedresponses, including the evoked neural and/or muscular responses.Stimulation parameters are set or adjusted to provide a stimulationintensity required for reliably activating the B-fibers.

FIG. 1 is an illustration of an embodiment of a vagus nerve stimulationsystem 100 and portions of an environment in which system 100 is used.System 100 includes a stimulation electrode 110, a stimulation outputcircuit 111, a control circuit 112, a neural sensing electrode 114A, alaryngeal activity sensor 114B, and an evoked response detection circuit116.

FIG. 1 shows a portion of vagus nerve 102 of a patient. Vagus nerve 102has branches including an RLN 106. Stimulation electrode 110 iselectrically connected to stimulation output circuit 111 and placed onvagus nerve 102 to allow for delivery of neurostimulation pulses fromstimulation output circuit 111 to modulate functions of the patient'sthoracic organs, including a heart 105, and/or abdominal organs that areinnervated by various branches of vagus nerve 102. In the illustratedembodiment, stimulation electrode 110 is placed on the cervical vagusnerve (the portion of vagus nerve 102 cranial to where RLN 106 branchesout). RLN 106 innervates laryngeal muscles (represented by a laryngealmuscle 107), which may contract in response to the neurostimulationpulses.

Responses evoked by the neurostimulation pulses are detected. In theillustrated embodiment, neural sensing electrode 114A is placed on vagusnerve 102 to sense evoked neural responses, and laryngeal activitysensor 114B is placed in or over laryngeal muscle 107 to sense evokedmuscular responses. Evoked response detection circuit 116 detects theevoked neural and/or muscular responses. In other embodiments, system110 includes either or both of neural sensing electrode 114A andlaryngeal activity sensor 114B to sense either or both of the evokedneural responses and the evoked muscular responses.

Control circuit 112 controls delivery of the neurostimulation pulsesfrom stimulation output circuit 111. In one embodiment, control circuit112 controls the delivery of the neurostimulation pulses using thedetected evoked neural and/or muscular responses to ensure that vagusnerve 102, or one or more of its branches, is activated as intended.

In various embodiments, the circuit of system 100, including its variouselements discussed in this document, is implemented using a combinationof hardware and software. In various embodiments, control circuit 112and/or evoked response detection circuit 116, including their variouselements discussed in this document, may be implemented using anapplication-specific circuit constructed to perform one or moreparticular functions or a general-purpose circuit programmed to performsuch function(s). Such a general-purpose circuit includes, but is notlimited to, a microprocessor or a portion thereof, a microcontroller orportions thereof, and a programmable logic circuit or a portion thereof.

FIG. 2 is a block diagram illustrating an embodiment of a vagus nervestimulation system 200. System 200 is an embodiment of system 100 andincludes stimulation electrodes 210, stimulation output circuit 111, anevoked response sensor 214, a sensor processing circuit 215, an evokedresponse detection circuit 216, a control circuit 212, and a storagecircuit 218.

Stimulation electrodes 210 include one or more stimulation electrodes tobe placed in the patient's body in one or more locations suitable fordelivering neurostimulation pulses to activate vagus nerve 102. Invarious embodiments, activation of vagus nerve 102 by theneurostimulation pulses includes activation of one or more portions orbranches of vagus nerve 102. In one embodiment, stimulation electrodes210 include stimulation electrode 110. In one embodiment, stimulationelectrodes 210 include one or more implantable stimulation electrodes,which are incorporated into one or more implantable leads each includingone or more conductors for electrically connecting the one or morestimulation electrodes to stimulation output circuit 111 In oneembodiment, stimulation electrodes 210 include one or more cuffelectrodes to be placed on vagus nerve 102. In one embodiment,stimulation electrodes 210 include at least a bipolar cuff electrode tobe placed on vagus nerve 102. In one embodiment, stimulation electrodes210 include a monopolar cuff electrode to be placed on vagus nerve 102and another stimulation electrode placed in or on the patient' body. Inone embodiment, stimulation electrodes 210 include at least amulti-contact electrode to be placed on or adjacent to vagus nerve 102.

Evoked response sensor 214 is to be placed in or on the patient' body ina location suitable for sensing a physiological signal indicative ofevoked responses being physiologic events evoked by the neurostimulationpulses. In one embodiment, evoked response sensor 214 includes neuralsensing electrode 114A to sense evoked neural responses including actionpotentials in vagus nerve 102 evoked by the neurostimulation pulses. Theevoked neural responses include evoked A-fiber responses and evokedB-fiber responses. The evoked A-fiber responses include actionpotentials in the A-fibers of vagus nerve 102 evoked by theneurostimulation pulses. The evoked B-fiber responses include actionpotentials in the B-fibers of vagus nerve 102 evoked by theneurostimulation pulses. In one embodiment, evoked response sensor 214includes laryngeal activity sensor 114B to sense an evoked muscularresponse including activities of laryngeal muscle 107 evoked by theneurostimulation pulses. In various embodiments, evoked response sensor214 includes either or both of neural sensing electrode 114A andlaryngeal activity sensor 114B. Sensor processing circuit 215 processesthe physiological signal in preparation for detection of the evokedresponses. Evoked response detection circuit 216 receives the processedphysiological signal from sensor processing circuit 215, detects theevoked responses using the processed physiological signal, and generatesone or more response signals representative of the detected evokedresponses. The one or more response signals includes information about,for example, whether vagus nerve 102 is captured by the neurostimulationpulses and measured characteristics of the evoked responses.

Control circuit 212 controls the delivery of the neurostimulation pulsesusing a stimulation intensity that is represented by one or morestimulation parameters such as a pulse amplitude and a pulse width. Thestimulation intensity is the energy in each of the neurostimulationpulses as measured by the pulse amplitude and the pulse width.

Control circuit 212 includes a parameter adjustor 220 to adjust thestimulation intensity by adjusting one or more stimulation parameters.In one embodiment, parameter adjustor 220 adjusts the one or morestimulation parameters using the one or more response signals generatedby evoked response detection circuit 216.

Storage circuit 218 stores the evoked responses in the form of one ormore waveforms of the evoked responses and the one or morecharacteristic parameters of the evoked responses. In one embodiment,storage circuit 218 stores the stimulation intensity associated withdetected evoked responses.

In various embodiments, the circuit of system 200, including variousembodiments of its elements as illustrated in FIG. 2, is programmed toperform the various functions discussed in this document. In variousembodiments, such functions allow for performance of the methodsincluding, but not limited to, those discussed with reference to FIGS.15, 16, and 18-20.

FIG. 3 is a block diagram illustrating an embodiment of a vagus nervestimulation system 300. System 300 is an embodiment of system 100 or 200and includes stimulation electrodes 210, stimulation output circuit 111,evoked response sensor 214, sensor processing circuit 215, an evokedresponse detection circuit 316, a control circuit 312, and storagecircuit 218.

Evoked response detection circuit 316 is an embodiment of evokedresponse detection circuit 216 and detects the evoked responses usingthe physiological signal and generates one or more response signalsrepresentative of the detected evoked responses. Evoked responsedetection circuit 316 includes a detection timer 326, a comparator 327,and a measurement module 328. Detection timer 326 controls timing ofdetection of the evoked responses. Examples of such timing includeinitiation of the detection according to a specified schedule and one ormore detection windows within which the evoked responses are expected tobe detected. Comparator 327 detects the evoked responses by comparingthe physiological signal to one or more detection thresholds. In oneembodiment, comparator 327 detects the evoked responses by comparing thephysiological signal to one or more detection thresholds during the oneor more detection windows. Measurement module 328 measures one or morecharacteristic parameters of the evoked responses. Examples of the oneor more characteristic parameters include amplitude of the evokedresponses, width of the evoked responses, and frequency characteristicsof the evoked responses. In various embodiments, the one or morecharacteristic parameters arc each a value measured from one of theevoked responses or being an average of values measured from a pluralityof the evoked responses. In various embodiments, examples of the one ormore response signals include a capture verification signal declaringcapture of the vagus nerve by the neurostimulation pulses and one ormore signals representative of the one or more characteristic parametersof the evoked responses.

Control circuit 312 is an embodiment of control circuit 212 and controlsthe delivery of the neurostimulation pulses using the stimulationintensity. Control circuit 312 includes a parameter adjustor 320, whichis an embodiment of parameter adjustor 220 and adjusts one or moreparameters of the stimulation parameters using the one or more responsesignals. In the illustrated embodiment, parameter adjustor 320 includesa sensing parameter adjustor 321, a sensing adjustment timer 322, astimulation parameter adjustor 323, and a stimulation adjustment timer324. Sensing parameter adjustor 321 adjusts the one or more detectionthresholds used by comparator 327 for detecting the evoked responses.Sensing adjustment timer 322 controls the timing of the adjustment ofthe one or more detection thresholds according to a specified scheduleand/or in response to a user command. Stimulation parameter adjustor 323adjusts the stimulation intensity by adjusting one or more of thestimulation parameters including either or both of the pulse amplitudeand the pulse width of the neurostimulation pulses. In variousembodiments, stimulation parameter adjustor 323 also adjusts otherstimulation parameters such as pulse frequency, duty cycle, andstimulation duration. Stimulation adjustment timer 324 controls thetiming of adjustment of the stimulation intensity according to aspecified schedule and/or in response to a user command.

FIG. 4 is an illustration of an embodiment of an implantable system 430and portions of an environment in which implantable system 430 is used.Implantable system 430 includes system 100 including its variousembodiments as discussed in this document.

System 430 includes an implantable system 432 and an external system436. Implantable system 432 includes an implantable medical device (IMD)434. External system 436 and IMD 434 communicate via a telemetry link435. In various embodiments, implantable system 432 includes system 200or system 300. In various embodiments, IMD 434 integrates a cardiacrhythm management (CRM) device with a neural sensing and stimulationdevice including portions of system 200 or portions of system 300. TheCRM device senses cardiac electrical activities and delivers cardiacstimulation. Examples of the CRM device include pacemakers,cardioverter/defibrillators, combinedpacemaker-cardioverter/defibrillators, cardiac resynchronization therapy(CRT) devices, and cardiac remodeling control therapy (RCT) devices. Invarious embodiments, neural activities are sensed to indicate a need forcardiac stimulation and/or to control the timing of pacing pulsedeliveries. In various embodiments, cardiac activities are sensed tocontrol the timing of neural stimulation pulse deliveries, such as tosynchronize neural stimulation to cardiac cycles.

FIG. 5 is a block diagram illustrating an embodiment of an implantablesystem 530. Implantable system 530 is an embodiment of implantablecircuit 430 and includes an IMD 534 and an external system 536.

IMD 534 is an embodiment of IMD 434 and includes an IMD circuit 539 andan implantable housing 538 encapsulating IMD circuit 539. In oneembodiment, IMD circuit 539 includes at least stimulation output circuit111 and control circuit 212 or 312. In another embodiment, IMD circuit539 includes at least stimulation output circuit 111, sensor processingcircuit 215, evoked response detection circuit 216 or 316, controlcircuit 212 or 312, and storage circuit 218. In various embodiments, IMDcircuit 539 includes various elements of system 200 or system 300.

External system 536 is an embodiment of external system 436 and iscommunicatively coupled to IMD 534 via telemeny link 435. Externalsystem 536 includes a user interface 540. User interface 540 includes apresentation device 542 and a user input device 544. Presentation device542 includes a display screen 543 to display, for example, waveforms ofthe detected evoked responses, the one or more response signals, themeasured one or more characteristics parameters, and/or the stimulationintensity. User input device 544 receives user commands from a user suchas a physician or other caregiver. Examples of the user commands includea user command for starting a delivery of the neurostimulation pulses, auser command to initiate an adjustment of the one or more detectionthresholds, a user command to initiate an adjustment of the stimulationintensity, and a user command to initiate automatic capture verificationas discussed in this document.

In one embodiment, external system 536 includes a programmer includinguser interface 540. In one embodiment, external system 536 includes apatient management system including an external device communicativelycoupled to IMD 534 via telemetry link 435 and a remote device in adistant location and communicatively coupled to the external device viaa communication network. The external device and/or the remote deviceinclude user interface 540.

FIG. 6 is an illustration of evoked responses to a neurostimlation pulsedelivered to the cervical vagus nerve as seen on a neural signalrecorded from the vagus nerve and an electromyographic (EMG) signalrecorded from a laryngeal muscle. The neural signal includes an evokedneural response that follows the delivery of the neurostimulation pulse.The time delay between the evoked neural response and the delivery ofthe neurostimulation pulse is a function of the distance between theneural signal sensing site and the stimulation site. The evoked neuralresponse includes an evoked A-fiber response and an evoked B-fiberresponse. As seen in FIG. 6, the evoked A-fiber response precedes theevoked B-fiber response. The EMG signal includes an evoked muscularresponse that follows the delivery of the neurostimulation pulse. Thetime delay between the evoked muscular response and the delivery of theneurostimulation pulse is a function of the distance between the EMGsignal sensing site and the stimulation site. In various embodiments,the time delays are estimated using the distance between the sensingsite and the stimulation site to facilitate the detection of the evokedresponses.

FIG. 7 is an illustration of evoked responses to nettrostimlation pulsesof various intensities. Neural and EMG signals including evoked neuraland muscular responses to neurostimulation pulses with different pulseamplitudes are shown. The morphology changes in the neural and EMGsignals indicate that more nerve fibers are captured as the pulseamplitude increases. The minimum pulse amplitude required to evoke theA-fiber and muscular responses is lower than the minimum pulse amplituderequired to evoke the B-fiber responses.

FIG. 8 is an illustration showing recruitment curves indicative ofvarious stimulation thresholds being the pulse amplitudes correspondingto percentage of fiber recruitment. The stimulation threshold curvesshow a trend consistent with what is observed from the neural and EMGsignals of FIG. 7. The evoked A-fiber responses start to be detectablewhen the stimulation (current) amplitude is about 0.8 mA. The evokedB-fiber responses start to be detectable when the stimulation amplitudeis between about 1.5 mA to 2 mA. It is believed that the A-fiberscorrespond to motor fibers of the vagus nerve that are primarilyresponsible for the activation of the laryngeal muscle, and the B-fiberscorrespond to part of the parasympathetic fibers of the vagus nerve thatare primarily responsible for the modulation of physiologic functionsincluding cardiovascular functions.

FIG. 9 is a block diagram illustrating an embodiment of a circuit fordetecting evoked neural responses. In one embodiment, the circuit ispart of IMD circuit 539.

The circuit includes stimulation output circuit 111, a neural sensingcircuit 915, and an evoked neural response detection circuit 916.Stimulation output circuit 111 delivers neurostimulation pulses to thevagus nerve. Neural sensing circuit 915 is an embodiment of sensorprocessing circuit 215 and senses a neural signal representative ofneural activities in the vagus nerve including evoked neural responseseach evoked by one of the neurostimulation pulses. Evoked neuralresponse detection circuit 916 is an embodiment of evoked responsedetection circuit 216 and detects the evoked neural responses using theneural signal. Evoked neural response detection circuit 916 includes adetection timer 926 and a comparator 927. Detection timer 926 times adelay interval, a detection window A, and a detection window B inresponse to delivery of one of the neurostimulation pulses. Asillustrated in FIG. 10, the delay interval starts upon the delivery ofthe one of the stimulation pulses. The detection window A, which is atime window within which an evoked A-fiber response is expected, startsupon expiration of the delay interval. The detection window B, which isa time window within which an evoked B-fiber response is expected,starts upon expiration of the detection interval A. Comparator 927detects the evoked A-fiber response by comparing the sensed neuralsignal to a detection threshold A during the detection window A anddetects the evoked B-fiber response by comparing the sensed neuralsignal to a detection threshold B during the detection window B. Inanother embodiment, evoked neural response detection circuit 916includes comparator 927 but not detection timer 926. Comparator 927detects the evoked neural responses by comparing the sensed neuralsignal to one or more detection thresholds.

FIG. 11 is a block diagram illustrating an embodiment of a system fordetecting evoked neural responses. The system includes stimulationelectrodes 210, stimulation output circuit 111, neural sensingelectrodes 1114, neural sensing circuit 915, and an evoked neuralresponse detection circuit 1116.

Neural sensing electrodes 1114 are an embodiment of evoked responsesensor 214 and are configured to be placed in the patient's body in alocation suitable for sensing the neural signal representative of neuralactivities in the vagus nerve including evoked neural responses eachevoked by one of the neurostimulation pulses.

In one embodiment, neural sensing electrodes 1114 include implantableneural sensing electrodes being part of implantable system 432. In oneembodiment, neural sensing electrodes 1114 include one or more cuffelectrodes to be placed on the vagus nerve. Neural sensing circuit 915is an embodiment of sensor processing circuit 215 and senses a neuralsignal through neural sensing electrodes 1114.

Evoked neural response detection circuit 1116 is an embodiment of evokedneural response detection circuit 916 and an embodiment of evokedresponse detection circuit 216 or 316 and detects the evoked neuralresponses using the sensed neural signal. Evoked neural responsedetection circuit 1116 includes at least comparator 927 and an evokedneural response measurement module 1128, and includes detection timer926 if at least one detection window is used. In various embodiments,evoked neural response detection circuit 1116 detects the evoked neuralresponse according to a specified schedule, such as on a periodic basis,or in response to a user command. Evoked neural response measurementmodule 1128 is an embodiment of measurement module 328 and measures oneor more characteristic parameters of the evoked neural responses. In oneembodiment, evoked neural response measurement module 1128 measures andtrends the one or more characteristic parameters. Examples of the one ormore characteristic parameters include amplitude of the evoked A-fiberresponse being the peak amplitude of the sensed neural signal during thedetection window A, width of the evoked A-fiber response being the timeinterval during which the amplitude of the sensed neural signal exceedsthe detection threshold A during the detection window A, amplitude ofthe evoked B-fiber response being the peak amplitude of the sensedneural signal during the detection window B, and width of the evokedB-fiber response being the time interval during which the amplitude ofthe sensed neural signal exceeds the detection threshold B during thedetection window B.

Experimental data from an animal study indicate that the amplitude ofthe evoked neural response in the detection window A (i.e., the evokedA-fiber response) is in a range of approximately 5 to 20 μV, and theevoked neural response in the detection window B (i.e., the evokedB-fiber response) is in a range of approximately 1 to 6 μV. During thestudy, the duration of the detection window A was set to 5 ms, and theduration of the detection window B was set to 5 ms. The delay interval,or timing for initiating each of the detection window A and thedetection window B depended on the distance between the stimulation siteand the sensing site.

If the stimulation site and the sensing site are close to each other, itmay be difficult to set the delay interval and the detection window Aaccurately. Consequently, it may be difficult to detect the evokedA-fiber response. However, detection of the evoke B-fiber responses isof primary interest because the B-fibers are believed to be responsiblefor modulating target functions of vagus nerve stimulation such ascardiovascular functions.

In one embodiment, the distance between the stimulation site and thesensing site is received from the user by user input device 544. In oneembodiment, the stimulation site is where a neural stimulation electrodeis placed on the vagus nerve, and the sensing site is where a neuralsensing electrode is placed on the vagus nerve. Detection timer 926determines the delay interval, the detection window A, and the detectionwindow B each as a function of that distance. In one embodiment, thelength of the delay interval, the detection window A, and the detectionwindow B are each calibrated using the time between a non-capturingelectrical neurostimulation pulse and a field effected by that pulse(not an evoked response).

FIG. 12 is a block diagram illustrating an embodiment of a circuit fordetecting evoked muscular responses. In one embodiment, the circuit ispart of IMD circuit 539.

The circuit includes stimulation output circuit 111, a laryngealactivity sensing circuit 1215, and an evoked muscular response detectioncircuit 1216. Stimulation output circuit 111 delivers neurostimulationpulses to the vagus nerve. Laryngeal activity sensing circuit 1215 is anembodiment of sensor processing circuit 215 and senses a laryngealsignal representative of activities of the laryngeal muscle includingevoked muscular responses each evoked by one of the neurostimulationpulses. Evoked muscular response detection circuit 1216 is an embodimentof evoked response detection circuit 216 and detects the evoked muscularresponses using the laryngeal signal. In the illustrated embodiment,evoked neural response detection circuit 1216 includes a detection timer1226 and a comparator 1227. Detection timer 1226 times a detectionwindow during which the detection of an evoked muscular response isanticipated. Comparator 1227 detects the evoked muscular responses bycomparing the sensed laryngeal signal to one or more detectionthresholds during the detection window. In another embodiment, evokedneural response detection circuit 1216 includes comparator 1227 but notdetection timer 1226. Comparator 1227 detects the evoked muscularresponses by comparing the sensed laryngeal signal to one or moredetection thresholds.

FIG. 13 is a block diagram illustrating an embodiment of a system fordetecting evoked muscular responses. The system includes stimulationelectrodes 210, stimulation output circuit 111, a laryngeal activitysensor 1314, laryngeal activity sensing circuit 1215, and an evokedmuscular response detection circuit 1316.

Laryngeal activity sensor 1314 is an embodiment of evoked responsesensor 214 and is configured to be placed in or on the patient's body ina location suitable for sensing the laryngeal signal. In one embodiment,laryngeal activity sensor 1314 includes an implantable laryngealactivity sensor to be placed in the patient's body. In anotherembodiment, laryngeal activity sensor 1314 includes an externallaryngeal activity sensor to be placed on the surface of the patient'sbody. Laryngeal activity sensing circuit 1215 is an embodiment of sensorprocessing circuit 215 and processes the signal sensed by laryngealactivity sensor 1314. Examples of the laryngeal signal, laryngealactivity sensor 1314, and laryngeal activity sensing circuit 1215 arediscussed below with reference to FIG. 14.

Evoked muscular response detection circuit 1316 is an embodiment ofevoked muscular response detection circuit 1216 and an embodiment ofevoked response detection circuit 216 or 316, and detects the evokedmuscular responses using the sensed laryngeal signal. Evoked muscularresponse detection circuit 1316 includes at least comparator 1227 and anevoked muscular response measurement module 1328, and includes detectiontimer 1226 if the detection window is used. In one embodiment, evokedmuscular response detection circuit 1316 detects the evoked muscularresponse according to a specified schedule, such as on a periodic basis,or in response to a user command. Evoked muscular response measurementmodule 1328 is an embodiment of measurement module 328 and measures oneor more characteristic parameters. In one embodiment, evoked muscularresponse measurement module 1328 measures and trends the one or morecharacteristic parameters. Examples of the one or more characteristicparameters include the amplitude of an evoked muscular response, the sumof multiple evoked muscular responses that follow multipleneurostimulation pulses, and the time between the delivery of aneurostimulation pulse and the detection of the evoked muscular responseresulting from the delivery of that neurostimulation pulse.

Amplitude of the evoked muscular responses increases as more motorfibers (A-fibers) are captured by delivery of the neurostimulationpulses. More motor fibers are captured as the stimulation intensityincreases.

It is believed that an approximately constant relationship can beidentified between the stimulation threshold for capturing the A-fibersand the stimulation threshold for effectively modulating a targetphysiological function through capturing the B-fibers. The stimulationintensity is a minimum stimulation intensity required to evoke one ormore specified physiological responses. Once an initial stimulationthreshold providing for the initial evoked muscular response isdetermined, the stimulation intensity is set to a level that isdetermined by using the initial stimulation threshold and the identifiedapproximately constant relationship. The initial evoked muscularresponse is the evoked muscular responses that start to becomedetectable as the stimulation intensity increases from a low initiallevel. The initial stimulation threshold is the stimulation intensitythat produces the initial evoked muscular response. In one embodiment,the approximately constant relationship is quantitatively establishedusing a patient population. The stimulation intensity for a vagus nervestimulation therapy applied to the patient is then set using the initialstimulation threshold and the established approximately constantrelationship.

FIG. 14 is a block diagram illustrating an embodiment of a circuit forsensing various laryngeal signals. The circuit includes a laryngealactivity sensor 1414 and a laryngeal activity sensing circuit 1415.Laryngeal activity sensor 1414 is an embodiment of laryngeal activitysensor 1314. Laryngeal activity sensing circuit 1415 is an embodiment oflaryngeal activity sensing circuit 1215. In the illustrated embodiment,laryngeal activity sensor 1414 includes EMG sensing electrodes 1414A, anaccelerometer 1414B, and a voice sensor 1414C, and laryngeal activitysensing circuit 1415 includes an EMG sensing circuit 1415A, an activitysensing circuit 1415B, and a voice sensing circuit 1415C. This allowsfor selection of a laryngeal signal by the user or the system of FIG.13, and also allows for use of multiple laryngeal signals for thedetection of the evoked muscular responses. In various embodiments,laryngeal activity sensor 1414 includes any one or more of EMG sensingelectrodes 1414A, accelerometer 1414B, and voice sensor 1414C, andlaryngeal activity sensing circuit 1415 includes the corresponding oneor more of

EMG sensing circuit 1415A, activity sensing circuit 1415B, and voicesensing circuit 1415C, depending on the laryngeal signal(s) used.

EMG sensing electrodes 1414A are configured to be placed in or on thepatient's body in a location suitable for sensing an EMG signal as thelaryngeal signal from laryngeal muscle 107. The EMG signal is indicativeof activities of laryngeal muscle 107 including the evoked muscularresponse. In one embodiment, EMG sensing electrodes 1414A includesimplantable EMG sensing electrodes such as intramuscular electrodes. EMGsensing circuit 1415A senses the EMG signal through EMG sensingelectrodes 1414A. Evoked muscular response detection circuit 1216 or1316 detects the evoked muscular responses using the sensed EMG

Accelerometer 1414B is configured to be placed in or on the patient'sbody in a location suitable for sensing an acceleration signal as thelaryngeal signal. The acceleration signal is indicative of activities oflaryngeal muscle 107 including the evoked muscular responses. In oneembodiment, accelerometer 1414B includes an implantable accelerometer.Activity sensing circuit 1415B processes the acceleration signal sensedby accelerometer 1414B. Evoked muscular response detection circuit 1216or 1316 detects the evoked muscular responses using the processedacceleration signal.

Voice sensor 1414C is configured to be placed in or on the patient'sbody in a location suitable for sensing a voice signal as the laryngealsignal. In one embodiment, voice sensor 1414C includes a microphone. Inone embodiment, voice sensor 1414C includes an implantable voice sensor.Vagus nerve stimulation is known to cause change in a patent's voice,such as hoarseness, by activating the laryngeal muscle. Thus, certainchanges in the voice signal are indicative of activities of laryngealmuscle 107 including the evoked neuromuscular responses. Voice sensingcircuit 1415C processes the voice signal sensed by voice sensor 1414C.Evoked muscular response detection circuit 1216 or 1316 detects theevoked muscular responses using the processed voice signal, such as bydetecting changes in frequency characteristics of the voice signal.

FIG. 15 is a flow chart illustrating an embodiment of a method 1500 forautomatic threshold adjustment (also referred to as “Auto-Sense”) forevoked response detection during vagus nerve stimulation. In variousembodiments, method 1500 is performed by using system 100, including itsvarious embodiments discussed in this document. The automatic thresholdadjustment provides automatic adjustment of the one or more detectionthresholds used by evoked response detection circuit 116, including itsvarious embodiments discussed in this document. In various embodiments,evoked response detection circuit 116 is configured to perform method1500 according to a specified schedule. In one embodiment, evokedresponse detection circuit 116 is configured to perform method 1500periodically, such as monthly, weekly, daily, hourly, once each burst ofthe neurostimulation pulses, or once each pulse of the neurostimulationpulses.

At 1502, neurostimulation pulses are delivered to a vagus nerve. At1504, a physiological signal is sensed. The physiological signal isindicative of evoked responses each being a physiologic event evoked byone of the neurostimulation pulses. At 1506, the evoked responses aredetected by comparing the physiological signal to one or more detectionthresholds. At 1508, the one or more detection thresholds are adjusted,if necessary, using the detected evoked neural responses.

In one embodiment, the physiological signal is sensed using evokedresponse sensor 214 and sensor processing circuit 215 at 1504. Theevoked responses are detected by evoked response detection circuit 316at 1506. The one or more detection thresholds are adjusted by sensingparameter adjustor 321. Sensing adjustment timer 322 times theperformance of method 1500 according to the specified schedule or inresponse to a user command.

In one embodiment, the physiological signal includes a neural signalrepresentative of neural activities in the vagus nerve including evokedneural responses each evoked by one of the neurostimulation pulses, andthe evoked responses include the evoked neural responses. At 1504, theneural signal is sensed. At 1506, the evoked neural responses aredetected. In one embodiment, an evoked neural response waveformrepresentative of the evoked neural responses is detected and stored.The waveform is of one detected evoked neural response or an average ofseveral detected evoked neural responses. In one embodiment, one or morecharacteristic parameters of the evoked neural responses are measured.Examples of the one or more characteristic parameters include theamplitude of the evoked A-fiber response, the width of the evokedA-fiber response, the amplitude of the evoked B-fiber response, and thewidth of the evoked B-fiber response as discussed above. In oneembodiment, the measured one or more characteristic parameters aretrended and/or stored for presentation to the user as scheduled orneeded. At 1506, the one or more detection thresholds, such as thedetection threshold A and the detection threshold B, are adjusted usingthe detected evoked neural responses. In one embodiment, the detectedevoked neural responses are compared to a stored baseline response. Thisincludes comparing the evoked neural response waveform to a storedbaseline waveform and/or comparing the one or more characteristicparameters to stored one or more baseline characteristic parameters. Thebaseline waveform and/or the one or more baseline characteristicparameters are established for a patient during the initial system setupfor the patient (such as implantation of implantable system 432), duringa follow-up visit, or automatically by evoked neural response detectioncircuit 916 when certain criteria are met. The one or more detectionthresholds are adjusted in response to the detected evoked neuralresponses substantially deviating from the stored baseline response. Inone embodiment, the user is alerted in response to the detected evokedneural responses substantially deviating from the stored baselineresponse.

In one embodiment, the physiological signal includes a laryngeal signalrepresentative of activities of the laryngeal muscle including evokedmuscular responses each evoked by one of the neurostimulation pulses,and the evoked responses includes the evoked muscular responses. At1504, the laryngeal signal is sensed. At 1506, the evoked muscularresponses are detected. In one embodiment, an evoked muscular responsewaveform representative of the evoked muscular responses is detected andstored. The waveform is of one detected evoked muscular response or anaverage of several detected evoked muscular responses. In oneembodiment, one or more characteristic parameters of the evoked muscularresponses are measured.

Examples of the one or more characteristic parameters include a maximumamplitude of the sensed laryngeal signal. In one embodiment, themeasured one or more characteristic parameters are trended and/or storedfor presentation to the user as scheduled or needed. At 1506, the one ormore detection thresholds are adjusted using the detected evokedmuscular responses. In one embodiment, the detected evoked muscularresponses are compared to a stored baseline response. This includescomparing the evoked response waveform to a stored baseline waveformand/or comparing the one or more characteristic parameters to stored oneor more baseline characteristic parameters. The baseline waveform and/orthe one or more baseline characteristic parameters are established for apatient during the initial system setup for the patient (such asimplantation of implantable system 432), during a follow-up visit, orautomatically by evoked muscular response detection circuit 916 whencertain criteria are met. The one or more detection thresholds areadjusted in response to the detected evoked muscular responsessubstantially deviating from the stored baseline response. In oneembodiment, the user is alerted in response to the detected evokedmuscular responses substantially deviating from the stored baselineresponse.

FIG. 16 is a flow chart illustrating an embodiment of a method 1600 foradjusting stimulation intensity for vagus nerve stimulation. In variousembodiments, method 1600 is performed by using system 100, including itsvarious embodiments discussed in this document.

At 1602, neurostimulation pulses are delivered to a vagus nerve. At1604, the delivery of the neurostimulation pulses is controlled using astimulation intensity. The stimulation intensity is adjustable byadjusting stimulation parameters including a pulse amplitude and a pulsewidth. At 1606, the stimulation intensity is swept at specifiedincrements. At 1608 a physiological signal is sensed. The physiologicalsignal is indicative of evoked responses each being a physiologic eventevoked by one of the neurostimulation pulses. At 1610, the evokedresponses are detected. At 1612, a stimulation threshold is determined.The stimulation threshold is a minimum level of the stimulationintensity for providing one or more specified characteristics of theevoked responses. At 1614, the stimulation intensity is adjusted formodulating a specified physiologic function using the stimulationthreshold. In one embodiment, the physiologic function includes acardiovascular function. In one embodiment, the stimulation thresholdmeasured from each performance of method 1600 is trended. In variousembodiments, the trend of the stimulation threshold is used to indicatepathological conditions and/or device problems. For example, asubstantially increasing stimulation threshold may indicate deviceproblems such as poor electrical connections or lead failure orpathological conditions such as nerve damages. When this happens, theuser is alerted for examining the patient and the neurostimulationsystem. If the stimulation threshold is not determined after thestimulation intensity is swept through its maximum level, the user isalso alerted because an abnormally high stimulation threshold isindicative of the device problems or pathological conditions.

In one embodiment, stimulation parameter adjustor 323 controls thesweeping of the stimulation intensity at 1606. The physiological signalis sensed using evoked response sensor 214 and sensor processing circuit215 at 1608. The evoked responses are detected by evoked responsedetection circuit 316 at 1610. The stimulation threshold is determinedby stimulation parameter adjustor 323 at 1612. The stimulation intensityis adjusted by stimulation parameter adjustor 323 at 1614. Stimulationadjustment tinier 324 initiates and/or times the performance of method1600 according to the specified schedule or in response to a usercommand.

In one embodiment, the physiological signal includes a neural signalrepresentative of neural activities in the vagus nerve including evokedneural responses each evoked by one of the neurostimulation pulses, andthe evoked responses include the evoked neural responses. At 1608, theneural signal is detected. At 1610, the evoked neural responses aredetected. In one embodiment, an evoked neural response waveformrepresentative of the evoked neural responses is detected and stored.The waveform is of one detected evoked neural response or an average ofseveral detected evoked neural responses. At 1612, the stimulationthreshold for one or more specified effects in the evoked neuralresponse is determined. Examples of the one or more specified effectsinclude that the amplitude of the sensed neural signal during thedetection window A reaches a threshold amplitude, that the width of theevoked response detected during the detection window A reaches athreshold width, that the evoked B-fiber response is detected during thedetection window B, and that a correlation between the detected evokedneural response waveform and a stored baseline waveform reaches athreshold correlation. At 1614, the stimulation intensity is adjustedfor modulating a specified physiologic function, such as acardiovascular function, using the stimulation threshold.

In one embodiment, the physiological signal includes a laryngeal signalrepresentative of activities of the laryngeal muscle including evokedmuscular responses each evoked by one of the neurostimulation pulses,and the evoked responses include the evoked muscular responses. At 1608,the laryngeal signal is detected. At 1610, the evoked muscular responsesare detected. In one embodiment, an evoked muscular response waveformrepresentative of the evoked muscular responses is detected and stored.The waveform is of one detected evoked muscular response or an averageof several detected evoked muscular responses. At 1612, the stimulationthreshold for one or more specified effects in the evoked muscularresponse is determined. Examples of the one or more specified effectsinclude that the amplitude of the sensed laryngeal signal during adetection window reaches a threshold amplitude, that an evoked muscularresponse is detected during the detection window, and a correlationbetween the detected evoked muscular response waveform and a storedbaseline waveform reaches a threshold correlation. At 1614, thestimulation intensity is adjusted for modulating a specified physiologicfunction, such as a cardiovascular function, using the stimulationthreshold.

In one embodiment, in which the sensed physiological signal includes thelaryngeal signal, the threshold amplitude is set to a minimum amplitudeof the laryngeal signal that allows for the detection of the evokedmuscular responses, and the corresponding stimulation threshold isrecorded as an initial stimulation threshold. The stimulation intensityis adjusted to a level calculated by using a predetermined relationshipbetween the initial stimulation threshold and a value of the stimulationintensity associated with the specified physiological function, such asthe cardiovascular function. Because it is believed that the A-fiberscorrespond to the motor fibers of the vagus nerve that are primarilyresponsible for the activation of the laryngeal muscle, and that theB-fibers correspond to part of the parasympathetic fibers of the vagusnerve that are primarily responsible for the modulation of physiologicfunctions including cardiovascular functions, the predeterminedrelationship is a relationship between the stimulation threshold foractivating the A-fibers (Threshold A) and the stimulation threshold foractivating the B-fibers (Threshold B). Experimental data indicate thatsuch a relationship can be approximated by a constant. FIG. 17 is anillustration showing an example of such a relationship. The plot showsnormalized dynamic ranges of a ratio of the difference between ThresholdB and Threshold A to the sum of Threshold B and Threshold A, i.e.,(Threshold B−Threshold A)/(Threshold B+Threshold A), for various pulsewidths, where Threshold A is the stimulation threshold for recruitingabout 50% of the A-fibers, and Threshold B is the stimulation thresholdfor recruiting about 50% of the B-fibers. Thus, the stimulationintensity is calculated by multiplying the initial stimulation thresholdby the constant.

In one embodiment, method 1600 is performed by system 100 automatically.This automatic stimulation intensity adjustment (also referred to as“Auto-Threshold”) provides automatic adjustment of the stimulationintensity for modulating the specified physiological function. Invarious embodiments, control circuit 112 and evoked response detectioncircuit 116, including their various embodiment as discussed in thisdocument, are configured to perform method 1600 according to a specifiedschedule. In one embodiment, control circuit 112 and evoked responsedetection circuit 116 are configured to perform method 1600periodically, such as monthly, weekly, daily, hourly, once each burst ofthe neurostimulation pulses, or once each pulse of the neurostimulationpulses, In other embodiments, adjustment of the stimulation intensity isperformed by the user using system 100, as discussed below withreference to FIGS. 18 and 19.

FIG. 18 is a flow chart illustrating an embodiment of a method 1800 foradjusting stimulation intensity for vagus nerve stimulation duringimplantation of an implantable medical device. In one embodiment, method1800 is performed by the user using system 100, including its variousembodiments discussed in this document.

At 1802, stimulation electrodes are placed on a vagus nerve of apatient. At 1804, the stimulation electrodes are connected to aneurostimulator including stimulation output circuit 111 and controlcircuit 112 for delivering neurostimulation pulses to the vagus nerve.The neurostimulator may be an external device for use during theimplantable procedure or the implantable medical device intended to beimplanted into the patient.

At 1806, an evoked response sensor is placed in the patient for sensinga physiological signal indicative of evoked responses each being aphysiologic event evoked by one of the neurostimulation pulses. Invarious embodiments, this includes placing neural sensing electrodes onthe vagus nerve for sensing a neural signal and/or placing a laryngealactivity sensor in a location suitable for sensing a laryngeal signal.The neural signal is representative of neural activities in the vagusnerve including evoked neural responses each evoked by one of theneurostimulation pulses. The laryngeal signal is representative ofactivities of the laryngeal muscle including evoked muscular responseseach evoked by one of the neurostimulation pulses. In variousembodiments, the evoked response sensor may be for temporary use duringthe implantation procedure or intended to be implanted with theimplantable medical device into the patient.

At 1808, the neurostimulation pulses are delivered through thestimulation electrodes. The delivery of the neurostimulation pulses iscontrolled using a stimulation intensity that starts at a specified lowlevel. The stimulation intensity is controlled by one or morestimulation parameters including the pulse amplitude and/or the pulsewidth. At 1810, the physiological signal is sensed.

At 1812, the evoked responses, including waveforms and measuredinformation, are presented to the user on a display screen. When thephysiological signal includes the neural signal, examples of thepresented information include amplitude of the evoked neural responses,sum of a plurality of the evoked neural responses, time between thedelivery of a neurostimulation pulse and the detection of the evokedneural response resulting from the delivery of that neurostimulationpulse, notation of response characteristics (e.g., “A-fiber” and“B-fiber” labels), and stimulation parameters including thosecontrolling the stimulation intensity. When the physiological signalincludes the laryngeal signal, examples of the presented informationinclude amplitude of the evoked muscular responses, sum of a pluralityof the evoked muscular responses, time between the delivery of aneurostimulation pulse and the detection of the evoked muscular responseresulting from the delivery of that neurostimulation pulse, andstimulation parameters including those controlling the stimulationintensity.

At 1816, if the user is not satisfied with the evoked neural responsesat 1814, the stimulation intensity is increased by increasing the pulseamplitude and/or the pulse width. If the stimulation intensity cannot befurther increased, the user is alerted for examining the patient forpossible pathological conditions preventing effectiveness ofneurostimulation and/or the system for possible device and/or connectionproblems. At 1818, if the user is satisfied with the evoked neuralresponses associated with a level of the stimulation intensity at 1814,that level of the stimulation intensity (in terms of the pulse amplitudeand the pulse width) is stored and used for the subsequent vagus nervestimulation therapy delivered from the implantable medical device. Theevoked response sensor is removed if it is for temporary use during theimplantation procedure.

FIG. 19 is a flow chart illustrating an embodiment of a method 1900 foradjusting stimulation intensity for vagus nerve stimulation duringfollow-up visits by the patient using the implantable medical device.Method 1900 is performed subsequent to method 1800. In one embodiment,method 1900 is performed by the user using system 100, including itsvarious embodiments discussed in this document.

At 1902, an intensity adjustment feature of the implantable medicaldevice is initiated by the user. In one embodiment, stimulationadjustment timer 423 initiates the adjustment of stimulation intensityin response to a user command entered by the user using an externalsystem communicatively coupled to the implantable medical device. At1904, stimulation intensity levels are swept. This includesincrementally increasing the pulse amplitude and/or the pulse width fromspecified low values.

At 1906, the physiological signal is sensed using the evoked responsesensor that was implanted in the patient with the implantable medicaldevice. This includes sensing of the neural signal and/or the laryngealsignal. At 1908, the evoked responses, including the evoked neuralresponses and/or the evoked muscular responses, are detected. At 1910,data representative of the detected evoked responses are telemetered tothe external system.

At 1912, the evoked responses, including waveforms and measuredinformation, are presented to the user on a display screen of theexternal system using the telemetered data. When the physiologicalsignal includes the neural signal, examples of the presented informationinclude amplitude of the evoked neural responses, sum of a plurality ofthe evoked neural responses, time between the delivery of aneurostimulation pulse and the detection of the evoked neural responseresulting from the delivery of that neurostimulation pulse, notation ofresponse characteristics (e.g., “A-fiber” and “B-fiber” labels), andstimulation parameters including those controlling the stimulationintensity. When the physiological signal includes the laryngeal signal,examples of the presented information include amplitude of the evokedmuscular responses, sum of a plurality of the evoked muscular responses,time between the delivery of a neurostimulation pulse and the detectionof the evoked muscular response resulting from the delivery of thatneurostimulation pulse, and stimulation parameters including thosecontrolling the stimulation intensity.

At 1916, if the user is not satisfied with the evoked neural responsesat 1914, the stimulation intensity is increased by increasing the pulseamplitude and/or the pulse width. If the stimulation intensity cannot befurther increased, the user is alerted for examining the patient forpossible pathological conditions preventing effectiveness ofneurostimulation and/or the system for possible device and/or connectionproblems. At 1918, if the user is satisfied with the evoked neuralresponses associated with a level of the stimulation intensity at 1914,that level of the stimulation intensity (in terms of the pulse amplitudeand the pulse width) is stored and used for the subsequent vagus nervestimulation therapy delivered from the implantable medical device.

FIG. 20 is a flow chart illustrating an embodiment of a method 2000 forautomatic capture verification (also referred to as “Auto-Capture”) forvagus nerve stimulation. In various embodiments, method 2000 isperformed by using system 100, including its various embodimentsdiscussed in this document. The automatic capture verification providesautomatic verification of capture of the vagus nerve by neurostimulationpulses and adjustment of the stimulation intensity. In variousembodiments, control circuit 112 and evoked response detection circuit116, including their various embodiments as discussed in this document,are configured to perform method 1600 according to a specified schedule.In one embodiment, control circuit 112 and evoked response detectioncircuit 116 are configured to perform method 1600 periodically, such asmonthly, weekly, daily, hourly, once each burst of the neurostimulationpulses, or once each pulse of the neurostimulation pulses.

At 2002, neurostimulation pulses are delivered to a vagus nerve. At2004, the delivery of the neurostimulation pulses is controlled using astimulation intensity. The stimulation intensity is adjusted byadjusting stimulation parameters including a pulse amplitude and a pulsewidth. At 2006, a capture verification is performed. The captureverification includes sensing a physiological signal indicative ofevoked responses each being a physiologic event evoked by one of theneurostimulation pulses at 2008, detecting one of the evoked responsesfor each pulse of the neurostimulation pulses delivered at 2010, andadjusting the stimulation intensity at 2012. The stimulation intensityis adjusted in response to specified one or more of the evoked responsesnot detected (i.e. non-capture) for a specified number of theneurostimulation pulses delivered. This includes adjustment of the pulseamplitude and/or the pulse width of the neurostimulation pulses. In oneembodiment, the stimulation intensity is adjusted in response to anevoked response not being detected for one of the neurostimulationpulses delivered. In another embodiment, the stimulation intensity isadjusted in response to the evoked response not being detected for aspecified first number of the neurostimulation pulses delivered out of aspecified second number of the neurostimulation pulses delivered. Inanother embodiment, the stimulation intensity is adjusted in response toan evoked response not being detected for a rolling average number ofthe neurostimulation pulses delivered. In one embodiment, method 2000 isperformed with the stimulation intensity lowered to prevent unnecessaryenergy delivered with the neurostimulation pulses to promote devicelongevity. If an unacceptable degree of loss of capture occurs when thestimulation intensity is set to about the available maximum level, theuser is alerted for examining the patient for possible pathologicalconditions preventing effectiveness of neurostimulation and/or thesystem for possible device and/or connection problems.

In one embodiment, stimulation parameter adjustor 323 controls thestimulation intensity at 2004. The physiological signal is sensed usingevoked response sensor 214 and sensor processing circuit 215 at 2008.The evoked responses are detected by evoked response detection circuit316 at 2010. The stimulation intensity is adjusted by stimulationparameter adjustor 323 at 2012. Stimulation adjustment timer 324initiates and/or times the performance of method 2000 according to thespecified schedule or in response to a user command.

In one embodiment, the physiological signal includes a neural signalrepresentative of neural activities in the vagus nerve including evokedneural responses each evoked by one of the neurostimulation pulses, andthe evoked responses include the evoked neural responses. At 2008, theneural signal is sensed. At 2010, one of the evoked neural responses foreach pulse of the neurostimulation pulses delivered is detected. At2012, the stimulation intensity is adjusted in response to specified oneor more of the evoked neural responses not detected (i.e. non-capture)for a specified number of the neurostimulation pulses delivered. In oneembodiment, the stimulation intensity is adjusted in response to anevoked neural response not being detected for one of theneurostimulation pulses delivered. In another embodiment, thestimulation intensity is adjusted in response to the evoked neuralresponse not being detected for a specified first number of theneurostimulation pulses delivered out of a specified second number ofthe neurostimulation pulses delivered. In another embodiment, thestimulation intensity is adjusted in response to an evoked neuralresponse not being detected for a rolling average number of theneurostimulation pulses delivered.

In one embodiment, the physiological signal includes a laryngeal signalrepresentative of activities of the laryngeal muscle including evokedmuscular responses each evoked by one of the neurostimulation pulses,and the evoked responses include the evoked muscular responses. At 2008,the laryngeal signal is sensed, At 2010, one of the evoked muscularresponses for each pulse of the neurostimulation pulses delivered isdetected. At 2012, the stimulation intensity is adjusted in response tospecified one or more of the evoked muscular responses not detected(i.e. non-capture) for a specified number of the neurostimulation pulsesdelivered. In one embodiment, the stimulation intensity is adjusted inresponse to an evoked muscular response not being detected for one ofthe neurostimulation pulses delivered. In another embodiment, thestimulation intensity is adjusted in response to the evoked muscularresponse not being detected for a specified first number of theneurostimulation pulses delivered out of a specified second number ofthe neurostimulation pulses delivered. In another embodiment, thestimulation intensity is adjusted in response to an evoked muscularresponse not being detected for a rolling average number of theneurostimulation pulses delivered.

In one embodiment, each of the automatic threshold adjustment(Auto-Sense), automatic stimulation intensity adjustment(Auto-Threshold), and automatic capture verification (Auto-Capture) isdisabled or delayed if noise in the sensed physiological signal exceedsa specified threshold noise level, due to the patient's activities andspeeches for example. In one embodiment, each of the automatic thresholdadjustment (Auto-Sense), automatic stimulation intensity adjustment(Auto-Threshold), and automatic capture verification (Auto-Capture) isperformed with various parameters such as the detection thresholdsadjusted for the patient's posture and activity level.

It is to be understood that the above detailed description is intendedto be illustrative, and not restrictive. Other embodiments will beapparent to those of skill in the art upon reading and understanding theabove description. The scope of the invention should, therefore, bedetermined with reference to the appended claims, along with the fullscope of equivalents to which such claims are entitled.

1. A system for delivering neurostimulation to a body having a vagus nerve and a laryngeal muscle, the system comprising: a stimulation output circuit configured to deliver neurostimulation pulses to the vagus nerve; an evoked response detection circuit configured to receive a physiological signal indicative of evoked responses being physiologic events evoked by the neurostimulation pulses and detect the evoked responses using the physiological signal and one or more detection thresholds; and a control circuit including a sensing parameter adjustor configured to adjust the one or more detection thresholds using the detected evoked responses and a stored baseline response.
 2. The system of claim 1, wherein the evoked response detection circuit is configured to generate one or more response signals representative of the detected evoked responses, and the control circuit is configured to control the delivery of the neurostimulation pulses using the one or more response signals.
 3. The system of claim 1, wherein the evoked response detection circuit comprises an evoked neural response detection circuit configured to receive a neural signal representative of neural activities in the vagus nerve including evoked neural responses each evoked by one of the neurostimulation pulses and detect the evoked neural responses using the one or more detection thresholds.
 4. The system of claim 1, wherein the evoked response detection circuit comprises an evoked muscular response detection circuit configured to receive a laryngeal signal representative of activities of the laryngeal muscle including evoked muscular responses each evoked by one of the neurostimulation pulses and detect the evoked muscular responses using the one or more detection thresholds.
 5. The system of claim 4, wherein the laryngeal signal comprises an electromyographic (EMG) signal, and comprising an EMG sensing circuit configured to sense the EMG signal.
 6. The system of claim 4, wherein the laryngeal signal comprises an acceleration signal, and comprising: an accelerometer configured to sensing the acceleration signal; and an activity sensing circuit configured to be coupled to the accelerometer to sense the acceleration signal.
 7. The system of claim 4, wherein the laryngeal signal comprises a voice signal, and comprising: a voice sensor configured to sensing the voice signal; and a voice sensing circuit configured to be coupled to the voice sensor to sense the voice signal.
 8. The system of claim 1, wherein the control circuit comprises a sensing adjustment timer configured to adjust the one or more detection thresholds using the detected evoked responses and the stored baseline response according to a specified schedule.
 9. The system of claim 1, comprising an implantable medical device including the neurostimulation output circuit, the evoked neural response detection circuit, and the control circuit.
 10. The system of claim 9, wherein the implantable medical device further includes a cardiac rhythm management device.
 11. A method for delivering neurostimulation to a body having a vagus nerve and a laryngeal muscle, the method comprising: delivering neurostimulation pulses to the vagus nerve; sensing a physiological signal indicative of evoked responses each being a physiologic event evoked by one of the neurostimulation pulses; detecting the evoked responses by comparing the physiological signal to one or more detection thresholds; and adjusting the one or more detection thresholds using the detected evoked responses.
 12. The method of claim 11, comprising: comparing the detected evoked responses to a stored baseline response; and adjusting the one or more detection thresholds using an outcome of the comparison of the detected evoked responses to the stored baseline response.
 13. The method of claim 12, wherein sensing the physiological signal comprises sensing a neural signal representative of neural activities in the vagus nerve including evoked neural responses each evoked by one of the neurostimulation pulses, detecting the evoked responses comprises detecting the evoked neural responses by comparing the neural signal to the one or more detection thresholds, and adjusting the one or more detection thresholds comprises adjusting the one or more detection thresholds using the detected evoked neural responses.
 14. The method of claim 12, wherein sensing the physiological signal comprises sensing a laryngeal signal representative of activities of the laryngeal muscle including evoked muscular responses each evoked by one of the neurostimulation pulses, detecting the evoked responses comprises detecting the evoked muscular responses by comparing the laryngeal signal to the one or more detection thresholds, and adjusting the one or more detection thresholds comprises adjusting the one or more detection thresholds using the detected evoked muscular responses.
 15. The method of claim 12, wherein comparing the detected evoked responses to the stored baseline response comprises: producing an evoked response waveform representative of the detected evoked responses; and comparing the evoked response waveform to a stored baseline waveform.
 16. The method of claim 12, wherein comparing the detected evoked responses to the stored baseline response comprises: measuring one or more characteristic parameters of the detected evoked responses; and comparing the one or more characteristic parameters to stored one or more baseline characteristic parameters.
 17. The method of claim 16, wherein measuring the one or more characteristic parameters of the detected evoked responses comprises measuring the one or more characteristic parameters each as an average value from the detected evoked responses.
 18. The method of claim 12, comprising producing an alert signal in response to the detected evoked responses substantially deviating from the stored baseline response.
 19. The method of claim 11, comprising adjusting the one or more detection thresholds according to a specified schedule.
 20. The method of claim 11, comprising adjusting the one or more detection thresholds in response to a user command. 